Targeting Glycogen Synthase Kinase-3 in the CNS: Implications for the Development of New Treatments for Mood Disorders
Todd D. Gould, Alyssa M. Picchini, Haim Einat and Husseini K. Manji
Affiliation: Laboratory of Molecular Pathophysiology, Bldg. 35, Room 1C-912, NIMH, NIH, Bethesda, MD 20892-3711, USA.
There exists an immediate need to develop novel medications for the treatment of mood disorders such as bipolar disorder and depression. Initial interest in glycogen synthase kinase-3 (GSK-3) as a target for the treatment of mood disorders arose from the finding that the mood stabilizing drug lithium directly inhibited the enzyme. More recent preclinical evidence implicates the modulation of GSK- 3 in either the direct or downstream mechanism of action of many other mood stabilizer and antidepressant medications currently in use. One of the cellular targets of GSK-3, which may mediate some of the effects of lithium and other drugs, is β-catenin, a transcription factor that is rapidly degraded when GSK-3 is active. Recent rodent behavioral data (both genetic and pharmacological) supports GSK-3 representing a therapeutically relevant target of lithium. This includes antidepressant-like behavior in the forced swim test and antimaniclike response to amphetamine following administration of the GSK-3 inhibitor AR-A014418, a findings that is concomitant with an increase in brain β-catenin. The evidence described in this review suggests that regulating GSK-3 may represent a target for novel medications to treat mood disorders.
Keywords: Manic-depressive illness, psychopharmacology, mania, depression, mood stabilizer, antidepressant, valproate
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